Abstract Title
Evaluation of MMV Pandemic Response Box compounds identifies MMP-inhibitor against HuNoV replication
Presenter
Myra Hosmillo, University of Cambridge
Co-Author(s)
Frédéric Sorgeloos, Armand-Frappier Santé Biotechnologie Research Centre, INRS, Canada
Ian Goodfellow, Division of Virology, Department of Pathology, University of Cambridge, UK
Abstract Category
Prevention & Control (antivirals)
Abstract
Human noroviruses (HuNoV) are recognized as the predominant cause of viral gastroenteritis globally, posing a substantial socio-economic burden across diverse geographical regions. The primary unmet need in norovirus treatment is the lack of specific antiviral therapies and vaccines beyond supportive care. There is an urgent need for effective treatments, particularly for high-risk groups like young children, elderly, and immunocompromised individuals, where norovirus infections can be severe. In addition, the ongoing challenges in culturing these viruses have been a major barrier to the development of targeted therapies and in-depth knowledge of the cellular processes that control virus infection.
Here, we developed a Nanoluc-based reporter replicon system for HuNoV GI in human gastric tumour (HGT)-cured cells and used this to evaluate 400 small molecules from the Medicines for Malaria Venture (MMV) pandemic box. This chemically diverse library, though originally designed to accelerate drug discovery for other pathogens, also serves as a rich source of chemical probes for investigating norovirus biology.
All compounds were screened by luciferease-based assay to quantify viral RNA replication, alongside a cytotoxicity assessment. Of the 400 tested, 13 compounds significantly modulated replication, either enhancing or suppressing reporter activity. Among these, a matrix metalloproteinase (MMP) inhibitor consistently reduced replicon replication. Follow-up testing with an additional MMP-targeting compound confirmed this effect. While the precise role of MMPs in the HuNoV life cycle remains to be elucidated, these findings suggest a possible involvement in virus–host interactions. Ongoing work is focused on defining the mechanism of action and exploring the broader relevance of MMPs in norovirus replication and persistence.
Here, we developed a Nanoluc-based reporter replicon system for HuNoV GI in human gastric tumour (HGT)-cured cells and used this to evaluate 400 small molecules from the Medicines for Malaria Venture (MMV) pandemic box. This chemically diverse library, though originally designed to accelerate drug discovery for other pathogens, also serves as a rich source of chemical probes for investigating norovirus biology.
All compounds were screened by luciferease-based assay to quantify viral RNA replication, alongside a cytotoxicity assessment. Of the 400 tested, 13 compounds significantly modulated replication, either enhancing or suppressing reporter activity. Among these, a matrix metalloproteinase (MMP) inhibitor consistently reduced replicon replication. Follow-up testing with an additional MMP-targeting compound confirmed this effect. While the precise role of MMPs in the HuNoV life cycle remains to be elucidated, these findings suggest a possible involvement in virus–host interactions. Ongoing work is focused on defining the mechanism of action and exploring the broader relevance of MMPs in norovirus replication and persistence.